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Weight cycling impairs pancreatic insulin secretion but does not perturb whole-body insulin action in diet-induced obese mice

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posted on 2022-07-08, 14:29 authored by Nathan C. Winn, Matthew A. Cottam, Monica Bhanot, Heather L. Caslin, Jamie N. Garcia, Rafael Arrojo e Drigo, Alyssa H. Hasty

In the setting of obesity and insulin resistance, glycemia is controlled in part by beta cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for b-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared to those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice 

Funding

This project was funded by a Veterans Affairs Merit Award 5I01BX002195 and an American Heart Association (AHA) Innovation Award (19IPLOI4760376) to AHH. MAC is supported by NIDDK (1F31DK123881) and was supported by METP (T32 DK007563-31) during data curation. NCW was supported by an American Physiological Society Postdoctoral Fellowship and the Molecular Endocrinology Training Program [METP, (T32 DK007563-31)] during data curation and analysis and is currently supported by the AHA (21POST834990). MB was supported by the Gastroenterology Training Grant (DK007673) and the AHA Strategically Focused Research Network award (17SFRN33520017) during data curation. HLC was supported by METP (T32 DK007563-31) during data curation and is currently supported by AHA (20POST35120547). JNG is supported by the METP (T32 DK007563-31). RAD is supported by Human Islet Research Network (U01DK120447) and dkNET New Investigator Pilot Program in Bioinformatics (5U24DK097771). AHH is supported by a Career Scientist Award from the Veterans Affairs (IK6 BX005649).

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